Binding energies of tyrosine kinase inhibitors: Error assessment of computational methods for imatinib and nilotinib binding

The binding energies of imatinib and nilotinib to tyrosine kinase have been determined by quantum mechanical (QM) computations, and compared with literature binding energy studies using molecular mechanics (MM). The potential errors in the computational methods include these critical factors:

• •Errors in X-ray structures such as structural distortions and steric clashes give unrealistically high van der Waals energies, and erroneous binding energies.
• •MM optimization gives a very different configuration to the QM optimization for nilotinib, whereas the imatinib ion gives similar configurations
• •Solvation energies are a major component of the overall binding energy. The QM based solvent model (PCM/SMD) gives different values from those used in the implicit PBSA solvent MM models. A major error in inhibitor—kinase binding lies in the non-polar solvation terms.
• •Solvent transfer free energies and the required empirical solvent accessible surface area factors for nilotinib and imatinib ion to give the transfer free energies have been reverse calculated. These values differ from those used in the MM PBSA studies.
• •An intertwined desolvation—conformational binding selectivity process is a balance of thermodynamic desolvation and intramolecular conformational kinetic control.
• •The configurational entropies (TΔS) are minor error sources.

     

Synthese et caracterisation de fluorotellurates IV alcalins et d'ammonium partie I. Etude du pentafluorotellurate IV de lithium LiTeF5

Lithium pentafluorotellurate (IV) LiTeF₅ has been prepared by different methods:

• •slow evaporation of a 1/1 mixture of lithium fluoride and tellurium dioxide or tellurium tetrachloride in anhydrous hydrogen fluoride,
• •heating a 1/1 mixture of lithium fluoride and tellurium tetrafluoride. LiTeF₅ is orthorhombic

(a = 9,52 Å b = 9,12 Å c = 11, 60 Å)     

Synthese et caracterisation de fluorotellurates IV alcalins et d'ammonium partie II: Etude des fluorotellurates d'ammonium NH4TeF5 et (NH4)2TeF6

New methods of synthesis:

• •reaction of aqueous or anhydrous HF with TeO₂ and NH₄F or NH₄HF₂, with (NH₄)₂TeCl₆
• •reaction of TeF₄ with NH₄F or NH₄HF₂
• •reaction of NH₄HF₂ with TeO₂

have been investigated for NH₄TeF₅ and a new compound (NH₄)₂TeF₆. The resulting compounds have been analysed and characterized.     

The adsorption of RNAse A,BSA and cytochrome c at the graphite powder|liquid interface using in parallel the adsorption isotherm plot and linear sweep voltammetry on graphite paste electrode

The adsorption of RNAse A, BSA and cytochrome c on graphite powder has been investigated using in parallel the adsorption isotherm plot and linear sweep voltammetry on a graphite paste electrode (g.p.e.). The principle of the latter depends on the determination by electrochemical oxidation of tyrosyl or tryptophan residues having access to the interface. Adsorption isotherms exhibit bimodal adsorption features with a cooperative phenomenon leading to the formation of a close-packed two dimensional surface phase. Protein molecules are adsorbed in a monolayer when the pH is different from the isoelectric point. This layer is built up by the entanglement of a double network:

• •A network of molecules irreversibly adsorbed side-on, where hydrophobic residues move from the core to the surface. The tertiary structure is likely altered. The new dimensions of these adsorbed molecules have been determined (surface area per molecule, thickness).
• •A network of molecules adsorbed end-on, lying between the irreversibly adsorbed molecules.

     

Conformational transitions in the regulation of cytochrome c oxidase activity

Oxidation of cytochrome c, catalyzed by cytochrome oxidase embedded in artificial liposomes of high respiratory control ratio (between 5 and 9.5), has been studied by rapid mixing techniques, under which conditions the enzyme undergoes a limited number of turnovers (from 1 to 5). The time course of the reaction could be satisfactorily simulated by a procedure derived from the concerted two-state model of Monod-Wyman-Changeux.The bulk of data and the novel analytical approach confirm the proposal that cytochrome oxidase undergoes a transition from a fast-reacting to a slow-reacting form as a consequence of the electrochemical gradient built up across the phospholipidic bilayer, and substantiate the idea that the conformational change:

• •occurs as an all-or-none process after about one turnover irrespective of the molar ratio between substrate and enzyme, and
• •is not immediately correlated to the other well known transition from the resting to the pulsed form of the enzyme.

     

Latest Developments in Proton Conductors

Solid proton conductors are receiving considerable attention, stimulated by the need of pollution control and with the objective to develop future microprotonics. The latest striking developments in the study of proton conductors are presented:

• i)Hydrogen containing perovskites, with a discussion of the nature and location of hydrogen inprotonic and electronic high-temperature superconductors;
• ii)Novel forms of hydrogen in disordered and mixed conductors, with the problems of the vibrational proton transfer assistance assumed by some authors and the independent proton dynamics evidenced by inelastic neutron scattering;
• iii)Frequency dependent conductivity and dielectric relaxation, including thermally stimulated current experiments in hydrated synthetic and biological gels (seeds);
• iv)Proton conducting membranes as candidates to replace Nafion®-like materials in H₂ (methanol) fuel cells.

     

Calorimetric studies of CeCu AND CeMgCu alloys

Using different calorimeters, the following measurements have been carried out.

• 1.(i) The integral enthalpies of mixing of CeCu binary and some CeMgCu ternary liquid alloys,
• 2.(ii) The enthalpy of formation and the enthalpy of melting of the intermetallic compound CeCu₂.
• 3.(iii) The heat content of solid and liquid CeCu₂.

The observed concentration and temperature dependence of the measured values of the enthalpies of mixing as well as the glass-forming abilities of these alloys are explained on the basis of an association model.     

Effects of static magnetic fields of erythrocyte rheology

The orientation of normal erythrocytes in a uniform static magnetic field (8 T maximum) has been investigated microscopically and photometrically.

• 1.(1) The intact erythrocytes were oriented with their disk planes parallel to the magnetic field because of the diamagnetism of the cell membrane components, particularly the transmembrane proteins (e.g., Band III, glycopholin) and the lipid bilayer.
• 2.(2) In contrast, the glutaraldehyde-fixed erythrocytes were oriented perpendicular to the field, perhaps because of the paramagnetism of the membrane-bound methemoglobin.
• 3.(3) The orientation was established within 5 s in a dilute suspension (5 × 10³cells μl⁻¹) as estimated from the change in light scattering after exposure to the magnetic field.

     

The kinetics of anion equilibration of human erythrocytes in phosphate-containing media of low chloride concentration

The pH-equilibration of human erythrocytes is accompanied by the transport of permeating anions. The kinetics of adaptation of erythrocytes to various outside solutions was investigated by continuous registration of extracellular pH and Cl⁻- and K⁺-concentration. In phosphate buffered solutions of low Cl⁻-content, the equilibration process consists of at least two components:

• •exchange of Cl⁻ for OH⁻ or HCO₃⁻;
• •exchange of Cl⁻ for phosphate

.The obtained time-dependence of extracellular pH and Cl⁻-concentration was fitted by means of a regression model which consists of two exponential terms assuming a fast and a slow transport component. By increasing of phosphate buffer concentration the fast time constant of Cl⁻- and pH-kinetics and the slow time constant of Cl⁻-kinetics were decreased whereas the slow pH-time constant was enhanced. CO₂-supply of the suspension tends to increase the slow time constant of pH- and Cl⁻-kinetics. These results can be explained by suggesting that the transport system is inhibited by phosphate or influenced by transmembrane potential.     

Application of radiation technology in biomedical materials; Fundamentals and applied

• 1.1) IMMOBILIZATION OF HEMOGLOBIN Hemoglobin has been immobilized into Poly Hema Matrix. To increase, Mechanical resistance, at first, CO was coodinated, after immobilization CO was eliminated by photo illumination by visible light from a W lamp and then O₂ was introduced. Oxygencoordiation ability was not damaged by immobilization.
• 2.2) REDUCTION MECHANISM OF ENZYME BY THE USE OF PULSE RADIOLYSIS Elementary process of Reduction Mechanism of Myoglobin, Hemoglobin, HRP and Cytochrome Oxidase were investigated in the time range of μsec≈nsec. In the of Cytochrome Oxidase, these are 4 metal ions inside of the Enzyme. The exact step of reduction of this enzyme was elucidated

.     

New experimental set-ups for studying nanoconfined water on the AILES beamline at SOLEIL

Three ensembles designed to investigate condensed matter in complex environments have been developed recently on the AILES beamline at SOLEIL. They have been exploited for studies aiming at understanding the properties of water molecules and their network in various confining systems, namely:

• -a hydration and temperature-controlled cell for the study of water confined in nanoporous Vycor,
• -a high pressure set-up allowing the study of the evolution of water molecules network trapped in Faujasite through the pressure-induced amorphisation of the matrix material,
• -a temperature resolved electrochemical cell used to record FIR difference spectra of metalloproteins interacting with water molecules.

By combining the high infrared flux and collimation of the AILES beamline with these optimized sample environments, it is possible to measure the infrared and THz spectra for minute quantities of samples in precise physical conditions.     

Recent studies of the interaction of rabbit dimeric IgA with its polymeric immunoglobulin receptor

Rabbit secretory components (SC) constitute a highly heteregeneous population of glycoprotein molecules that are present in secretions as free or bound forms to polymeric immunoglobulins (Ig). Two SC families are known, one of high molecular weight (⋍ 80 Kd) composed of five (perhaps six) domains related to Ig variable domains, and one of low molecular weight (⋍ 55 Kd) An account of our most recent experimental data is reviewed in this article. We have shown:

• 1.1) that both the high and low Mr SC families possess the same relative avidity for binding to dimeric IgA of the g-sublanguage;
• 2.2) that the first NH₂-terminal domain of SC derived from the high and low Mr polypeptides is necessary and sufficient for efficient non-covalent binding to dimeric IgA of the g-sublanguage;
• 3.3) that the low Mr SC polypeptide derives from the high Mr SC by the internal deletion of the entire second and third domains, suggesting that these domains are not involved in the binding reaction with polymeric Ig;
• 4.4) that the heterogeneity of rabbit secretory components is, in large part, due to the expression of several polymorphic forms (allotypes) susceptible to be recognized by specific alloantisera; the biochemical characterization of the three known SC allotypes (t61, t62 and t63) reveals that t62 and t63 are structurally very similar to each other and markedly divergent from the t61 homologue;
• 5.5) that by using non-cross-reactive alloantisera, the major immunodominant allotopes are confined within the COOH-terminal domains 3, 4 and 5 of SC;
• 6.6) that the location of the residues involved in the attachment of the carbohydrate unit within domain 1 varies according to the allotype: t61 is N-linked glycosylated at position 70, whereas about 75 % of t62 molecules are devoid of sugars; the remaining 25 % of t62 molecules are glycosylated at residue position 90; these oligosaccharide chain units are linked to asparagine residues in the acceptor site consensus sequence, Asn-X-Thr/Ser;
• 7.7) that the presence of the carbohydrate unit in domain 1 is not required for efficient binding of this domain to polymeric Ig: indeed, after enzymatic deglycosylation, domain 1 exhibits a relative binding avidity which is indistinguishable from that of the native glycosylated domain 1.

     

Thermal analysis and microstructure of solids and solid state reactions

Thermoanalytical and microstructural measurement techniques allow the characterization of solids, their transformation, decomposition, specific surface and pore structure. These techniques are of importance for solids with high specific surface and/or porosity. Thermoanalytical techniques are applied to detect solid state reactions, to determine reaction temperatures and to monitor the progress of the reaction. They are useful to simulate thermal processes in the industry and to receive meaningful results with small samples in a short time. Specific surface, cumulative pore volume and pore volume distribution are obtained by intrusion and absorption techniques. Here selected applications of thermoanalytical and microstructure investigations in modern fields of materials research will be presented, as:

-pore analysis of sintering steps of ceramics,

-secondary structure of catalyst granules,

-template decomposition in zeolites,

-firing process in a composide ceramic tape,

-ignition of coke.

     

899 — A potentiometric study on the redox properties of hemoglobin from Camelus dromedarius

A potentiometric study of the redox properties of hemoglobin from Camelus dromedarius has been performed, with the aim of having a better insight in the structure-function relationships of this protein; data on human hemoglobin have been included for comparative purposes. Analysis of the experimental data has shown:

• 1.the existence of intermediate conformers (neither R nor T) in the oxidized form of dromedary hemoglobin;
• 2.the amino acid groups involved in the oxidation Bohr effect of dromedary and human hemoglobins are likely to be the same; thus, only invariant amino acid residues seem to be involved in this effect.

     

N–H stretching frequencies and the conformation of substituted ureas: an ab initio MO study

The dependence of N–H stretching-mode frequencies in representative di- and trialkyl ureas on the conformational state of the ureido group has been studied by ab initio MO calculations using HF/3-21G and HF/6-31G** basis sets. The molecules studied were 1,3-dimethylurea, 1-methyl-3,3-dimethylurea and 1-methyl-3,3-di-iso-propylurea. The principal conclusions from the ab initio results are:

• 1.the trans–trans conformer (N–H bonds trans to the CO bond) has N–H stretching bands with about 20–30 cm⁻¹ higher frequency than the respective cis–cis structure, in accord with earlier literature assignments based on experimental data;
• 2.the N–H stretching frequency interval in tri-substituted ureas is 15–20 cm⁻¹ higher than the N–H band position in the 1,3-disubstituted molecule studied, the effect being determined mostly by the higher N–H stretching force constant;
• 3.in the absence of the steric hindrance the stable rotameric forms of the ureido grouping are almost planar at HF/3-21G level of calculations, while HF/6-31G** calculations predict a slightly pyramidal structure at the nitrogen atoms in the trans–trans conformer;
• 4.in 1-methyl-3,3-di-iso-propylurea the steric influence of the two bulky iso-propyl groups cause a deviation from planarity of the N–H bond. The non-planar conformation is accompanied by a shift of the N–H stretching mode frequency towards higher values; and
• 5.the variations of the theoretically estimated N–H stretching-mode frequencies appear to be principally determined by changes in the N–H stretching force constants in the different molecules.

© 1997 Elsevier Science B.V.     

On ion-pair photoseparation and recombination in micellar aggregates

Perylene (Pe) and tetramethylbenzidine (TMB) have been photoionized under continuous or laser pulse excitation in cationic (Mi⁺), neutral (Mi⁰) or anionic micelles (Mi^-). In the latter case, Mi^- composed of sodium dodecyl sulfate (SDS) surfactant molecules have been swollen upon the addition of various hydrocarbons and the interfacial electric potential ΔΨ modified by electrolyte addition.From previous and present data, the following conclusions can be drawn:

• •(a) Intramicellar ultrafast geminate recombinations are promoted by increasing the micellar volume but counteracted when high electron mobility values characterize the swelling agent;
• •(b) Recombinations involving the hydrated electron ρ^-_aq appear to be suppressed in negatively as well as in positively charged Mi and to occur in Mi⁰ to an extent depending upon the chromophore cation;
• •(c) The overall photoionization yield ø_ion of Pe or TMB is found to increase linearly as ΔΨ becomes more negative; such ΔΨ variation is shown to affect ø_ion through the primary electron ejection stage though the ionization threshold energy does not seem to be appreciably modified;
• •(d) For Mi^- aggregates, the photoionization efficiency curves ø_ion=f(λ) show a linear dependence on the photon excess energy in the threshold region; within such an energy range, the ø_ion(λ) curves would thus approximate the variation with λ of a primary ionization yield of the solute;
• •(e) As a corollary, it may be suggested that the shape of the ø_ion(λ) curves relative to homogeneous liquid solutions would be essentially governed by solute cation-ρ^-_solv recombination reactions.

     

Experimental characterization of gaseous species emitted by the fast pyrolysis of biomass and polyethylene

This study aims to experimentally characterize the carbonaceous and nitrogenous species, from the flash pyrolysis of millet stalks and polyethylene plastic bags, using the device of the tubular kiln, coupled to two gas analyzers: Analyzer Fourier Transform Infrared (FTIR) and an analyzer Infrared Non-Dispersive (IRND). Gaseous products analyzed are: CH₄, C₂H₂, C₂H₄, C₃H₈, C₆H₆, CO, CO₂, NO₂, NO, N₂O, HCN and NH₃. Whatever the temperature of thermal degradation, the pyrolysis shows us that in terms of mass:

• •For the millet stalks, the gaseous compounds are formed mainly CO and CO₂ to the carbonaceous species, HCN and NH₃, for the nitrogenous species analyzed;
• •As regards the polyethylene bags, hydrocarbons for carbonaceous species and HCN, NH₃ and NO₂ for the nitrogenous species, are most abundant.

In addition, the results suppose that in our experimental conditions, the hydrocarbon which is involved primarily in the formation of CO is ethylene C₂H₄. At the end of this characterization, we determined the rate of carbon and nitrogen found in the volatile gas. With millet stalks we have about 45% of volatile carbon and 15% of the nitrogen of fuel that are found in gaseous products. The results obtained with the plastic bags give 68% carbon and 15% nitrogen found in the nitrogenous species analyzed.     

Modeling and Flowsheet Design of an Am Separation Process Using TODGA and H4TPAEN

Recycling americium from spent fuels is an important consideration for the future nuclear fuel cycle, as americium is the main contributor to the long-term radiotoxicity and heat power of the final waste, after separation of uranium and plutonium using the PUREX process. The separation of americium alone from a PUREX raffinate can be achieved by co-extracting lanthanide (Ln(III)) and actinide (An(III)) cations into an organic phase containing the diglycolamide extractant TODGA, and then stripping Am(III) with selectivity towards Cm(III) and lanthanides. The water soluble ligand H₄TPAEN was tested to selectively strip Am from a loaded organic phase.Based on experimental data obtained by Jülich, NNL and CEA laboratories since 2013, a phenomenological model has been developed to simulate the behavior of americium, curium and lanthanides during their extraction by TODGA and their complexation by H₄TPAEN (complex stoichiometry, extraction and complexation constants, kinetics). The model was gradually implemented in the PAREX code and helped to narrow down the best operating conditions. Thus, the following modifications of initial operating conditions were proposed:

• •An increase in the concentration of TPAEN as much as the solubility limit allows.
• •An improvement of the lanthanide scrubbing from the americium flow by adding nitrates to the aqueous phase.

A qualification of the model was begun by comparing on the one hand constants determined with the model to those measured experimentally, and on the other hand, simulation results and experimental data on new independent batch experiments.A first sensitivity analysis identified which parameter has the most dominant effect on the process. A flowsheet was proposed for a spiked test in centrifugal contactors performed with a simulated PUREX raffinate with trace amounts of Am and Cm. If the feasibility of the process is confirmed, the results of this test will be used to consolidate the model and to design a flowsheet for a test on a genuine PUREX raffinate. This work is the result of collaborations in the framework of the SACSESS European Project.